This invention relates to a novel method of treatment using amoxycillin and for novel formulations, in particular tablet formulations, for use in such methods.
Amoxycillin is a well known xcex2-lactam antibiotic which has been available for many years. Despite the suspectibility of amoxycillin to inhibition by xcex2-lactamases produced by resistant organisms, amoxycillin still enjoys widespread usage as a broad spectrum antibiotic for the treatment of commonly occurring bacterial infections. In particular, amoxycillin is particularly effective in treating sore throatsxe2x80x94acute bacterial tonsillitis and/or pharyngitis where the causative organism is almost exclusively Streptococcus pyogenes. 
Amoxycillin is available commercially in a variety of formulations, for instance as capsules containing either 250 or 500 mg amoxycillin, as tablets comprising 500 or 875 mg amoxycillin, as chewable tablets comprising either 125 or 250 mg amoxycillin and as dry powder formulation, for reconstitution into an oral suspension. Other formulation types include dispersible tablets providing 500 mg amoxycillin, chewable effervescent tablets, comprising 125, 250 or 500 mg amoxycillin and single dose sachets comprising 750 or 3000 mg amoxycillin. The standard adult dosage is 250 mg. three times daily (tid), increasing to 500 mg tid for more severe infections. In addition, the 875 mg tablet is intended for dosing twice daily (bid), as an alternative to the dosage regimen of 500 mg tid. Recently, a 1000 mg chewing tablet has been advertised as being under development (AC Pharma, see SCRIP No 2472 Sep. 15, 1999, page 11). A high dosage of 3 g, bid, is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract. For short course therapy, in simple urinary tract infections, two 3 g doses, at an interval of 10-12 hours, are given while for a dental abscess, the dosage is two 3 g doses at an interval of 8 h and for gonorrhoea, a single dose of 3 g. Furthermore, the use of 1 g of amoxycillin, bid, is used as one arm of a combination therapy, for eradication of Helicobacter pylori in peptic ulcer disease.
In addition, amoxycillin is provided in combination with the xcex2-lactamase inhibitor potassium clavulanate, in various tablet formulations of amoxycillin and potassium clavulanate comprising various different weights and ratios of amoxycillin and potassium clavulanate, for instance, conventional swallow tablets comprising 250/125, 500/125, 500/62.5, and 875/125 mg amoxycillin/clavulanic acid (in the form of potassium clavulanate). Such tablets comprise amoxycillin and clavulanic acid in the ratio 2:1, 4:1, 8:1 and 7:1, respectively. The 875/125 mg tablet was developed to provide a tablet formulation which could be administered in a bid (twice daily) dosage regimen It is also marketed for tid (three times daily) dosing, in Italy and Spain. The 500/62.5 mg tablet was also developed to provide a tablet formulation which could be administered in a bid dosage regimen, two such tablets being taken every 12 h, in preference to a single 1000/125 mg tablet. A 1000/125 mg single dosage is also available, in France, but as a single dosage sachet rather than a tablet. Typically, the approved regimen provides a single dosage of 125 mg of potassium clavulanate.
In addition, WO 97/09042 (SmithKline Beecham) describes tablet formulations comprising amoxycillin and clavulanic acid in a ratio in the range 12:1 to 20:1, preferably 14:1. Furthermore, it is suggested that the preferred dosage of 1750/125 mg may be provided as two tablets, the first comprising 875/125 mg amoxycillin and clavulanic acid and the second 875 mg amoxycillin. The 14:1 ratio is said to be useful for the empiric treatment of bacterial infection potentially caused by drug resistant S pneumoniae (DRSP). This patent application also describes paediatric formulations comprising amoxycillin and clavulanate in a 14:1 ratio, for administering amoxycillin dosages of 90 mg/kg/day. Data suggest that such a dosage may provide antibiotic concentrations sufficient to eradicate DRSP with amoxycillin +/xe2x88x92clavulanic acid MICsxe2x89xa64 xcexcg/ml (Bottenfield et al, Pediatr Infect Dis J, 1998, 17, 963-8).
Existing marketed tablet formulations of amoxycillin are conventional in that they provide immediate release of the active ingredients once the tablet reaches the stomach. There has also been some interest in developing formulations in which the release profile is modified, to allow for a longer interval between dosages, for instances, every 12 hours (bid, q12 h), rather than every 8 hours (tid, q8 h).
Thus, for instance, WO 94/06416 (Jagotec AG) describes multi-layered tablets comprising 500 mg of amoxycillin distributed equally between an immediate release and a slow release layer. Furthermore, WO 95/20946 (SmithKline Beecham) describes inter alia a layered tablet comprising about 500 mg amoxycillin having a first layer which is an immediate release layer and a second layer which is a slow release layer, the ratio of amoxycillin between the two layers being about 1:2.6, as well as an intermediate barrier layer. Further bilayered tablets comprising clavulanic acid and amoxycillin are described in WO 98/05305 (Quadrant Holdings Ltd). In such tablets, a first layer comprises amoxycillin and a second layer comprises clavulanate and the excipient trehalose, to stabilise the clavulanate component.
In addition, WO 95/28148 (SmithKline Beecham) describes inter alia tablet formulations comprising amoxycillin and, optionally, clavulanate having a core comprising amoxycillin coated with a release retarding agent and surrounded by an outer casing layer of amoxycillin and potassium clavulanate. The release retarding agent is an enteric coating, so that there is a immediate release of the contents of the outer core, followed by a second phase from the core which is delayed until the core reaches the intestine. Furthermore, WO 96/04908 (SmithKline Beecham) describes inter alia tablet formulations comprising amoxycillin in a matrix, for immediate release, and granules in a delayed release form comprising amoxycillin. Such granules are coated with an enteric coating, so release is delayed until the granules reach the intestine. WO 96/04908 (SmithKline Beecham) describes inter alia delayed or sustained release formulations of amoxycillin formed from granules which have a core comprising amoxycillin and surrounded by a layer comprising amoxycillin.
In addition, WO 94/27557 (SmithKline Beecham) describes controlled release formulations of amoxycillin and clavulanic acid prepared using a hydrophobic waxy material which is then subjected to thermal infusion.
Further controlled release formulations comprising amoxycillin have been described by several groups. Thus, Arancibia et al ((Int J of Clin Pharm, Ther and Tox, 1987, 25, 97-100) describe the pharmacokinetic properties and bioavailability of a controlled release formulation comprising 500 mg of amoxycillin. No further details of the formulation are provided. The formulation was however designed to release 21 to 35% during the first 60 minutes, 51 to 66% at 4 hours, 70 to 80% at 6 hours, 81 to 90% at 8 hours and more than 94% at 12 hours. They however found little, if any, correlation between the in vitro dissolution rate and the pharmacokinetic behaviour in the body. Hilton et al (International Journal of Pharmaceutics, 1992, 86, 79-88) described an alternative controlled release tablet having a hydrophilic polymer matrix and a gas release system, to provide intragastric buoyancy, to enhance gastric retention time. This showed no advantage over a conventional capsule formulation, with bioavailability being diminished. In contrast, Hilton et al (Journal of Pharmaceutical Sciences, 1993, 82, 737-743) described a 750 mg controlled release tablet incorporating the enteric polymer hydroxypropylmethyl cellulose acetate succinate. This however failed to show any advantage over a conventional capsule. In particular, the bioavailability was reduced to 64.6% compared with the same dosage provided in a capsule. More recently, Hoffman et al (Journal of Controlled Release, 1998, 54, 29-37 and WO 98/22091) have described a tablet comprising 500 mg of amoxycillin in a matrix comprising hydroxypropyl methyl cellulose, designed to release 50% of its contents in the first three hours and complete the drug release process over eight hours. The time above MIC was found to be significantly extended, compared to a capsule formulation, but not enough for a 12 h dosing interval. The discussion is in the context of a theoretical MIC of 0.2 xcexcg/ml.
The present invention relates to a method of treating bacterial infections in humans which comprises administering thereto a therapeutically effective amount of amoxycillin in the range 1900 to 2600 mg, at a dosage regimen/interval of about 12 hours. Suitably, the infection is caused by the organisms S pneumoniae (including Drug Resistant and Penicillin Resistant S pneumoniae), H influenzae M catarrhalis and/or S Pyogenes. 
The present invention also relates to a modified, release pharmaceutical formulation comprising amoxycillin in which a first part of amoxycillin are formulated with pharmaceutically acceptable excipients which allow for immediate release of the first part of amoxycillin, to form an immediate release phase, and further comprising a second part of amoxycillin formulated with pharmaceutically acceptable excipients which allow for slow release of the second part of amoxycillin, to form a slow release phase.
The present invention also relates to an immediate release pharmaceutical tablet formulation comprising 1000 mgxc2x15% amoxycillin in combination with pharmaceutically acceptable excipients or carriers.
The present invention also relates to an immediate release pharmaceutical formulation in the form of a single dose sachet comprising 2000, 2250 or 2500 mgxc2x15% amoxycillin, or the corresponding half quantities thereof, in combination with pharmaceutically acceptable excipients or carriers.
Other suitable modified or immediate release formulations are described herein in greater detail.